Molecular dynamics of metabolism during perinatal liver development

我们利用胆道闭锁（BA）患者的血液样本和肝组织研究FGF19信号通路在慢性胆汁淤积症中的作用。BA患者血清胆汁酸浓度显著高于BA患者，FGF19血清和组织浓度显著高于BA患者。IHC和ISH显示，FGF19在BA肝细胞中异常合成。而在BA患者中，尽管胆汁酸和FGF19浓度较高，但这些靶基因CYP7A1mRNA并未受到抑制。接下来，BA患者肝细胞中FXR mRNA显著上调，FGFR4和KLB mRNA也上调。此外，BA患者中FGFR4的磷酸化水平升高，ERK的磷酸化水平降低。而在BA患者中，抑制CYP7A1的SHP mRNA表达上调。这些结果表明FGF19在慢性胆汁淤积型肝细胞中异常表达。然而，该信号不能通过ERK途径抑制CYP7A1。

We studied FGF19 signaling pathway in chronic cholestasis using blood sample and liver tissue from Biliary atresia (BA) patients. Serum concentration of bile acid was significantly higher in BA patients, and their serum and tissue concentrations of FGF19 were significantly higher in BA patients. IHC and ISH revealed that FGF19 were aberrantly synthesized in hepatocytes in BA liver. While, those target gene, CYP7A1mRNA was not suppressed in BA patients despite of high concentration of bile acid and FGF19. Next, FXR mRNA was significantly up-regulated in hepatocytes in BA patients, and FGFR4 and KLB mRNA were also up-regulated. Further, phosphorylation of FGFR4 in BA patients was increased, then phosphorylation of ERK was decreased. Whereas, SHP mRNA, which suppress CYP7A1 was up-regulated in BA patients. These results suggest that FGF19 was aberrantly expressed in chronic cholestatic hepatocytes. however, this signal was not able to suppress CYP7A1 via ERK pathway.